Obesity, syndrome X, and type 2 diabetes are increasing in prevalence and represent major causes of premature morbidity and mortality in westernized socities. The insulin resistance characterizing these diverse pathologies frequently results in a compensatory and sustained hyperinsulinemia. Chronically high insulin, apart from stimulating glucose uptake, has also been shown to be a powerfully activate sympathetic nerve activity (SNA). Importantly, elevated SNA produces several pathophysiological effects, including hypertension, atherosclerosis, ventricular hypertrophy, insulin resistance, and end-organ damage. These actions may partly explain why insulin is powerful and independent predictor of atherosclerosis and cardiovascular events. It remains unclear, however, what mechanisms mediate the excitatory effect of insulin on SNA. We and others have examined the possibility that insulin activates brain renin-angiotensin to then cause increases in sympathetic outflow. This hypothesis is based on the following evidence: 1) systemically-infused insulin increases SNA, 2) insulin penetrates into the brain to bind with insulin-specific receptors, 3) direct administration of insulin into the brain increases lumbar SNA, 4) insulin activates several components of the renin-angiotensin system, 5) insulin-induced SNA elevations are abolished by systemic or by intracerebroventricular renin-angiotensin blockade, 6) insulin-activated sympathetic increases are also abolished by lesions of the anteroventral third ventricle (AV3V) region, which is a primary site for the sympathoexcitatory actions of angiotensin II, and 7) renin-angiotensin pathways from AV3V nuclei to the paraventricular nucleus (PVN) exert powerful control over sympathetic output. Altogether, these findings indicate that insulin-induced sympathoexcitation is dependent upon components of the brain renin-angiotensin system. To extend these findings, the present studies will first, determine whether angiotensin II receptor antagonism in the organum vasculosum of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO), and PVN abolish increases in SNA to acute insulin, and second, will determine whether chronic SNA increases, activated by long-term insulin infusion or by high dietary fructose, are abolished by inhibition of brain renin-angiotensin using intracerebroventricular losartan. Finally, we will determine whether physiologically generated modulations of renin-angiotensin function, produced by altering dietary sodium intake, will affect acute sympathoexcitatory responses to insulin. By demonstrating the precise role of brain renin-angiotensin in eliciting SNA increases to hyperinsulinemia, the present experiments will provide fundamental new information regarding central neural regulation of autonomic output. In addition, these findings will generate new hypotheses for intervention strategies to prevent the deleterious consequences of sympathoexcitation in disease states characterized by insulin resistance and hyperinsulinemia.